Role of AT1 angiotensin II receptors in renal ischemic injury.
The present studies determined the effect of renal ischemia/reperfusion on components of the intrarenal renin-angiotensin system in rats and evaluated the effect of AT1 angiotensin (ANG) II receptor blockade on functional recovery. After bilateral renal pedicle occlusion for 60 min, serum creatinine increased, peaking at 72 h, and returned to sham levels after 120 h. ANG II levels in ischemic kidneys were significantly increased 24 h after reperfusion but did not differ from levels in sham kidneys after 120 h. Both renal cortical angiotensinogen mRNA and proximal tubular AT1 receptor mRNA were significantly reduced early after reperfusion, returning to sham levels by 120 and 72 h, respectively. AT2 ANG II receptor mRNA was undetectable in proximal tubules from sham rats but was consistently present in ischemic rats at 120 h. By histoautoradiography, we found that binding of 125I-labeled ANG II was preserved in glomeruli but was decreased in whole cortex and outer medulla early after reperfusion and was completely blocked by the AT1 antagonist losartan. Treatment of rats with losartan (25 mg/kg s.c. daily), starting at the time of reperfusion, had no effect on expression of proliferating cell nuclear antigen in cortical tubules but caused a significant decrease in serum creatinine at 72 h (ischemia: 334 +/- 69 microM vs. ischemia + losartan: 135 +/- 28 microM; P < 0.025, n = 6). These data indicate that renal ischemic injury causes an early increase in intrarenal ANG II levels, associated with reduction of mRNA for angiotensinogen and proximal tubular AT1 receptors, and maintenance of glomerular ANG II binding. Losartan accelerates recovery of renal function, suggesting that activation of AT1 receptors impairs glomerular filtration in the postischemic kidney.
Kontogiannis
J
J
Department of Medicine, University of Ottawa, Ontario, Canada.
Burns
K D
KD
D000804:Angiotensin II / Q000378:metabolism*; D000808:Angiotensinogen / Q000096:biosynthesis; D000818:Animals; D003404:Creatinine / Q000097:blood; D007511:Ischemia / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply* / Q000502:physiology / Q000503:physiopathology; D007672:Kidney Cortex / Q000502:physiology / Q000503:physiopathology; D007679:Kidney Medulla / Q000502:physiology / Q000503:physiopathology; D007687:Kidney Tubules, Proximal / Q000098:blood supply / Q000502:physiology / Q000503:physiopathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000096:biosynthesis / Q000378:metabolism*; D012016:Reference Values; D015424:Reperfusion; D014158:Transcription, Genetic; D015854:Up-Regulation
D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000808:Angiotensinogen; D000804:Angiotensin II; D003404:Creatinine; D019808:Losartan